Small molecule screening in context: lipid-catalyzed amyloid formation

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Islet Amyloid Polypeptide (IAPP) is co-secreted with insulin by pancreatic β-cells.
• IAPP amyloid fiber aggregation is linked to β-cell dysfunction and death in type II diabetes.
• IAPP toxicity may involve cell membrane penetration and depolarization, accelerated by lipid bilayers.

Purpose of the Study:

• To develop a high-throughput screening protocol to identify compounds targeting membrane-active IAPP species.
• To leverage the correlation between amyloid formation and toxicity for drug discovery.

Main Methods:

• A novel high-throughput screening protocol was established.
• The protocol utilizes lipid bilayer-catalyzed IAPP assembly.
• A library of 960 known bioactive compounds was screened.

Main Results:

• 37 compounds were identified as active against IAPP fiber formation.
• 36 of the identified compounds were novel in their activity against IAPP.
• Several compounds demonstrated cytoprotective effects in cell viability assays.

Conclusions:

• The developed screening protocol effectively identifies compounds targeting membrane-active IAPP species.
• This approach can discover mechanistically informative small molecules for amyloid diseases.
• The findings offer potential therapeutic strategies for type II diabetes and other amyloid-related disorders.